Submission Details

Primary Ciliary Dyskinesia (PCD) is a genetically heterogeneous group of disorders, usually beginning in early childhood, characterized by recurrent infections of the upper and lower respiratory tract, randomization of left/right body asymmetry, and in some cases infertility and hydrocephalus (PMID: 32943623). The PCD phenotype results from structural and/or functional abnormalities of motile cilia and flagella.

A mutation was first reported in the MCIDAS (Multiciliate Differentiation and DNA Synthesis-Associated Cell Cycle Protein) gene in association with a rare mucociliary clearance disorder characterized by reduced generation of multiple motile cilia (RGMC) in a study by Boon et al., 2014 (PMID: 25048963). Multiciliated cells (MCCs) are specialized epithelial cells with hundreds of motile cilia. In humans, MCCs are present in the choroid plexus and the ependyma of the brain to drive the circulation of cerebrospinal spinal fluid, in respiratory epithelial cells to assist in mucociliary clearance, and in the efferent ducts and oviducts for spermatozoa and egg transport (PMID: 32362381). MCIDAS is a transcriptional co-activator that regulates multiciliogenesis in epithelial cells (PMIDs: 24934224, 22231168). Patients with defective MCIDAS genes exhibit RGMC and present with a PCD phenotype that includes recurrent upper and lower respiratory tract infections as well as in most cases hydrocephalus and/or subfertility. Patients with RGMC do not have situs abnormalities. Some of the reported cases of MCIDAS-associated RGMC presented with a severe clinical phenotype, including premature mortality, oxygen dependency and severe lung disease (PMID: 25048963). Transmission electron microscopy images in these patients show severely reduced basal bodies in defective efferent duct and respiratory epithelial cells (PMIDs: 34569065, 25048963). The basal body is required to support the generation of the ciliary axoneme (PMID: 32362381). The rare residual cilia that are formed in patients with defective MCIDAS genes lack axonemal motility-related proteins (e.g. DNAH5, CCDC39) and are immotile (PMID: 25048963). The specific disease entity, Primary Ciliary Dyskinesia 42, without situs inversus is an autosomal recessive disorder caused by biallelic mutation in the MCIDAS gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and autosomal recessive mode of inheritance to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited MCIDAS variants have been lumped into a single disease entity, Primary Ciliary Dyskinesia 42, without situs inversus (MONDO: 0032872, OMIM # 618695).

Evidence from 9 probands in 5 publications (PMIDs: 25048963, 30237576, 32802948, 31879361, 34569065) have been included in this curation representing 8 unique variants (2 missense, 2 nonsense, 2 frameshift, and 2 splice site). Of note, all 9 probands, many from consanguineous families, were homozygous for MCIDAS mutations. The mechanism of pathogenicity in MCIDAS mutations appears to be biallelic loss of function. No other variants were found in the publicly available literature at the time of this curation. The variants in this curation were used to reach the maximum score for genetic evidence (12 points).

MCIDAS has been characterized as a transcriptional co-activator of MCC differentiation (PMID: 25048963, 24932224). Gene expression studies at different time points during ciliogenesis in cultured human nasal epithelial cells show that MCIDAS expression increases during MCC generation. Protein expression studies similarly show that MCIDAS is expressed and localizes to the nucleus of cells destined for MCC differentiation but is absent or weakly expressed in fully differentiated ciliated respiratory cells (PMID: 25048963). In contrast to CCNO mutant cells (PMID: 24747639), MCIDAS mutant cells lack the axonemal motility-related proteins DNAH5 and CCDC39, indicating that in MCIDAS mutant cells not only the number of MMCs is severely reduced, but the expression of ciliary motility-related proteins is also disrupted. FOXJ1, a transcriptional controller of ciliary motility-related proteins, was also absent in MCIDAS mutant cells (PMID: 25048963). Two studies of PCD patients homozygous for different MCIDAS variants, found that in the absence of functional MCIDAS, affected respiratory epithelial cells had no or at most one or two cilia (PMIDs: 33795320, 25048963). Reduced or absent multiciliated respiratory epithelial cells results in reduced mucociliary clearance, leading to the recurrent respiratory infections seen in PCD patients. MCCs in the efferent ducts of males play an important role in spermatozoa transport. One male PCD patient carrying homozygous MCIDAS mutations was shown to have efferent ducts mostly devoid of MCCs and was diagnosed with obstructive azoospermia. Immunofluorescence staining showed the absence of MCIDAS signal in the affected efferent ducts of this proband (PMID: 34569065). One of the other phenotypes associated with PCD 42 is hydrocephalus. Mcidas in situ hybridization studies as well as immunofluorescent microscopy of mice embryos confirm that Mcidas mRNA and protein are expressed in a restricted pattern in the mouse developing brain: the cortical hem and the choroid plexus epithelium of the telencephalic midline (PMID: 21543332). This pattern of expression in mice is consistent with a role for MCIDAS in the differentiation of both mouse and human brain MCCs.

Experiments in Xenopus laevis embryos show that Multicilin (MCIDAS) acts as a transcriptional activator for genes involved in centriole/basal body amplification and cilia formation by forming a ternary complex with E2f4 (or E2f5) and Dp1, the EDM complex (PMID: 24934224). Multicilin, on its own, lacks a DNA binding domain. When in complex with E2f4, a transcription factor, and its dimerization partner, Dp1, Multicilin is able to act as a transcriptional regulator. This complex formation is mediated through a 45-amino-acid region at the Multicilin C-terminus, called the TIRT domain. Two animal models support a gene disease association between MCIDAS and Primary Ciliary Dyskinesia 42. Morpholino knockdown of mcidas in X. laevis embryos resulted in the absence or severely reduced numbers of cilia (PMID: 22231168). Mcidas knockout mice developed hydrocephalus and failed to breed, suggesting infertility. These mice had a complete loss of MCCs in trachea, oviducts, and brain ependyma (PMID: 30877126).

In summary, there is definitive evidence supporting a gene-disease relationship between variants in MCIDAS and Primary Ciliary Dyskinesia 42. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on December 20, 2022 (SOP Version 9).